Publications by authors named "Thomas C Dowling"

46 Publications

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma.

Cancer Chemother Pharmacol 2021 Jun 15. Epub 2021 Jun 15.

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 400 Monroe Ave, NW, Grand Rapids, MI, 49503, USA.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor α-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment.

Methods: We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice.

Results: The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-Rb), suggesting DFMO/probenecid-induced cell cycle arrest.

Conclusion: Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.
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http://dx.doi.org/10.1007/s00280-021-04309-yDOI Listing
June 2021

Stimulating and sustaining scholarly activity at teaching-intensive institutions.

Curr Pharm Teach Learn 2021 Mar 15;13(3):228-237. Epub 2020 Dec 15.

Roseman University of Health Sciences College of Graduate Studies, 11 Sunset Way, Henderson, Nevada, 89014, United States; Roseman University of Health Sciences College of Pharmacy, 11 Sunset Way, Henderson, NV 89014, United States. Electronic address:

Introduction: Research and scholarship are core elements of the academic mission. Yet fulfilling institutional and accreditation requirements for scholarly activity can be challenging, particularly for teaching-intensive institutions. This paper describes strategies for employing a teacher-scholar model to stimulate and sustain scholarly activity.

Methods: Metrics of scholarly productivity were programmatically assessed and reported for at least five years following implementation of sixteen different strategic initiatives at three teaching-intensive colleges of pharmacy. Data reported included publications (original peer-reviewed publications, case reports, review articles), presentations (posters, podiums, and continuing education sessions), peer-reviewed published abstracts, grants awarded, and total extramural funding per annum. Faculty and student engagement in scholarship was indicated by authorship on at least one scholarly work.

Results: Broad increases in metrics of scholarly productivity were observed, while the timing and degree of change varied (1.4-fold to 10.4-fold, across all institutions, all years). Notably, the most robust growth was observed in grantsmanship and the number of faculty and student contributors to scholarly works. A key observation was that increased scholarly output was sustained, as during the most recent three-year period publications increased 1.6-fold, grants and extramural funding increased 3.4- and 15.8-fold, respectively, and faculty and student contributors increased 1.8- and 4.5-fold, respectively.

Conclusions: Overall, these data point to a substantive, detailed approach for increasing scholarship at diverse, teaching-intensive institutions by implementing cost-conscious strategies, including clear ties between scholarly effort/productivity and faculty performance/advancement, strong faculty development and mentoring, institutional commitments to infrastructure and research budgets, and student engagement in scholarly activities.
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http://dx.doi.org/10.1016/j.cptl.2020.10.005DOI Listing
March 2021

Metabolomic biomarkers are associated with mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

Future Sci OA 2019 Dec 17;6(2):FSO441. Epub 2019 Dec 17.

Margaret M & Albert B Alkek Department of Medicine, Section of Gastroenterology & Hepatology, Baylor College of Medicine, Houston, TX, USA.

Aim: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis.

Materials & Methods: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses.

Results: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392).

Conclusion: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers.
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http://dx.doi.org/10.2144/fsoa-2019-0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997913PMC
December 2019

Etoposide and etoposide phosphate hypersensitivity in children: Incidence, risk factors, and prevention strategies.

J Oncol Pharm Pract 2020 Mar 18;26(2):397-405. Epub 2019 Jul 18.

Ferris State University, College of Pharmacy, Big Rapids, MI, USA.

Introduction: Etoposide is critical in treating pediatric cancers, although hypersensitivity can be severe and treatment-limiting. Reported rates of hypersensitivity range from 2% to 51%. Hypersensitivity data for etoposide phosphate, a newer product, are lacking. The primary objective of this study was to assess etoposide and etoposide phosphate hypersensitivity incidence. Secondary objectives included evaluation of potential risk factors for hypersensitivity and strategies to prevent recurrence.

Methods: This retrospective cohort study evaluated pediatric patients who received initial etoposide phosphate or etoposide dose between August 2012 and July 2017. The primary outcome was documentation of hypersensitivity within four months of initial dose. Potential risk factors evaluated included age, allergies, dose, infusion rate, infusion concentration, and premedication.

Results: Of 246 patients, hypersensitivity reactions occurred in five of 54 patients (9.3%) who received etoposide phosphate and 52 of 192 patients (27.1%) who received etoposide ( = 0.0061). For etoposide, the mean initial infusion rate was 64.6 ± 40.9 mg/m/h for patients with hypersensitivity and 49.5 ± 33.4 mg/m/h without hypersensitivity ( = 0.0886). Etoposide phosphate rate was not associated with hypersensitivity. Recurrent hypersensitivity occurred in one of nine patients (11.1%) who received etoposide desensitization and one of 38 patients (2.6%) who changed formulation to etoposide phosphate.

Conclusions: Etoposide was associated with more hypersensitivity than etoposide phosphate in pediatric patients. Etoposide hypersensitivity was associated with higher infusion rates, but not etoposide phosphate. Differences in hypersensitivity incidence and infusion rate influence indicate a formulation-effect. Etoposide hypersensitivity recurrence may be prevented by changing to etoposide phosphate formulation. During etoposide phosphate shortages, etoposide desensitization may prevent recurrent hypersensitivity.
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http://dx.doi.org/10.1177/1078155219858390DOI Listing
March 2020

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

Dig Dis Sci 2018 03 1;63(3):665-675. Epub 2018 Feb 1.

Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX, 77030, USA.

Background: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction.

Aim: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates.

Methods: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines.

Results: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism.

Conclusions: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.
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http://dx.doi.org/10.1007/s10620-017-4897-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994910PMC
March 2018

Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis.

Transl Res 2018 05 12;195:25-47. Epub 2017 Dec 12.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Electronic address:

The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.
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http://dx.doi.org/10.1016/j.trsl.2017.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037419PMC
May 2018

Targeting of CDK9 with indirubin 3'-monoxime safely and durably reduces HIV viremia in chronically infected humanized mice.

PLoS One 2017 17;12(8):e0183425. Epub 2017 Aug 17.

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.

Successful propagation of HIV in the human host requires entry into a permissive cell, reverse transcription of viral RNA, integration into the human genome, transcription of the integrated provirus, and assembly/release of new virus particles. Currently, there are antiretrovirals against each of these viral steps, except for provirus transcription. An inhibitor of HIV transcription could both increase potency of treatment and suppress drug-resistant strains. Cellular cyclin-dependent kinase 9 (CDK9) serves as a cofactor for the HIV Tat protein and is required for effective transcription of the provirus. Previous studies have shown that the CDK9 inhibitor Indirubin 3'-monoxime (IM) inhibits HIV transcription in vitro and in short-term in vivo studies of HIV acute infection in humanized mice (PBMC-NSG model), suggesting a therapeutic potential. The objective of this study is to evaluate the toxicity, pharmacokinetics and long-term antiviral activity of IM during chronic HIV infection in humanized mice (HSC-NSG model). We show that IM concentrations above EC50 values are rapidly achieved and sustained for > 3 h in plasma, and that non-toxic concentrations durably reduce HIV RNA levels. In addition, IM enhanced the antiviral activity of antiretrovirals from the reverse transcriptase, protease and integrase inhibitor classes in in vitro infectivity assays. In summary, IM may enhance current antiretroviral treatments and could help achieve a "functional cure" in HIV patients by preventing expression of proviruses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183425PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560554PMC
October 2017

Reply to "On the Effect of Common Excipients on the Oral Absorption of Class 3 Drugs".

J Pharm Sci 2016 Apr;105(4):1355-7

Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201. Electronic address:

We previously concluded that 12 common excipients need not be qualitatively the same and quantitatively very similar to reference for Biopharmaceutics Classification System-based biowaivers. This conclusion for regulatory relief is based upon a series of bioequivalence studies in humans involving cimetidine and acyclovir. Limitations were also discussed. We understand the major concern of García-Arieta et al. is that "results obtained by Vaithianathan et al. should not be extrapolated to other drugs." We understand that individuals conducting their own risk/benefit analysis may reach that conclusion, and we reply to the concerns of García-Arieta et al. We continue to conclude that the 12 common excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather, simply be not more than the quantities studied in our manuscript for cimetidine and acyclovir, and potentially other class 3 drugs with similar properties.
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http://dx.doi.org/10.1016/j.xphs.2016.02.028DOI Listing
April 2016

Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir.

J Pharm Sci 2016 Feb 12;105(2):996-1005. Epub 2016 Jan 12.

Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201. Electronic address:

The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.
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http://dx.doi.org/10.1002/jps.24643DOI Listing
February 2016

Validation of a Dosing Strategy for Cefazolin for Surgery Requiring Cardiopulmonary Bypass.

Surg Infect (Larchmt) 2015 Dec 20;16(6):829-32. Epub 2015 Aug 20.

3 University of Maryland School of Medicine , Baltimore, Maryland.

Background: A prospective, single center, open-label study was conducted to determine if the standard practice for surgical prophylaxis, which includes standardized dosing of cefazolin, at the University of Maryland Medical Center (UMMC) is adequate for patients placed on bypass during cardiac surgery.

Methods: All patients were given the same standard dosing regimen regardless of weight: two grams of cefazolin administered within 1 h of incision, an additional one gram injected into the bypass circuit at the onset of bypass, and two grams every 3 h after the initial dose. Cefazolin serum concentrations were collected immediately after incision, after the start of bypass, each hour of bypass, at the end of bypass and at sternal closure.

Results: Ten patients were consented and completed the study with an average age of 62 y, average weight of 84.7 kg and average cardiopulmonary bypass time of 116 min. The free serum concentrations of cefazolin stayed above the pre-defined inhibitory threshold of 16 mcg/mL throughout the procedure for 100% of participants. The mean total serum concentration in the blood throughout surgery was 160 mcg/mL. No patients were found to have surgical site infections using standard criteria and no adverse events were observed.

Conclusions: For patients undergoing cardiac surgery with cardiopulmonary bypass, the UMMC dosing regimen surpassed targeted cefazolin concentrations during the entire surgical procedure for all patients regardless of weight or time on bypass.
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http://dx.doi.org/10.1089/sur.2014.250DOI Listing
December 2015

Influence of kidney disease on drug disposition: An assessment of industry studies submitted to the FDA for new chemical entities 1999-2010.

J Clin Pharmacol 2016 Apr 23;56(4):390-8. Epub 2015 Sep 23.

Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ, USA.

In 1998, the United States Food and Drug Administration (FDA) released the first guidance for industry regarding pharmacokinetic (PK) studies in renally impaired patients. This study aimed to determine if the FDA renal PK guidance influenced the frequency and rigor of renal studies conducted for new chemical entities (NCEs). FDA-approved package inserts (APIs) and clinical pharmacology review documents were analyzed for 194 NCEs approved from 1999 to 2010. Renal studies were conducted in 71.6% of NCEs approved from 1999 to 2010, a significant increase over the 56.3% conducted from 1996 to 1997 (P = .0242). Renal studies were more likely to be completed in highly renally excreted drugs (fe ≥ 30%) compared with drugs with low renal excretion, fe < 30% (89.6% vs 65.8%, P = .0015). PK studies to assess the impact of dialysis were conducted for 31.7% of NCEs that had a renal study: a greater proportion of high fe NCEs were studied (44.2% vs 26.0%, P = .0335). No significant change in frequency or rigor of PK studies was detected over time. The majority of NCEs (76.3%) with a renal study provided specific dosing recommendations in the API. The adoption of the 1998 FDA guidance has resulted in improved availability of PK and drug-dosing recommendations, particularly for high fe drugs.
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http://dx.doi.org/10.1002/jcph.604DOI Listing
April 2016

Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child-Turcotte-Pugh Class C Cirrhosis and Renal Dysfunction.

Dig Dis Sci 2015 Nov 5;60(11):3491-4. Epub 2015 Jul 5.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD, 21201, USA.

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http://dx.doi.org/10.1007/s10620-015-3771-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623880PMC
November 2015

Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines.

Clin Gastroenterol Hepatol 2016 Apr 29;14(4):624-632.e2. Epub 2015 Jun 29.

Department of Medicine, Howard University College of Medicine, Washington, District of Columbia.

Background & Aims: Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis.

Methods: From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, β-trace protein, β2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy.

Results: After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004).

Conclusions: We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.
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http://dx.doi.org/10.1016/j.cgh.2015.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695320PMC
April 2016

Performance of a divided-load intravenous vancomycin dosing strategy for obese patients.

Ann Pharmacother 2015 Aug 18;49(8):861-8. Epub 2015 May 18.

University of Manchester, Manchester, UK.

Background: Current guidelines recommend vancomycin trough concentrations of 15 to 20 µg/mL in complicated infections and all trough concentrations >10 µg/mL to avoid developing microbial resistance. To date, no published protocol reliably meets these recommendations for obese patients.

Objective: We assessed the performance of a novel, obese-specific, divided-load vancomycin protocol for attaining target trough concentrations within 12 to 24 hours of dosing initiation, and during maintenance dosing, in obese patients.

Methods: The protocol was evaluated through prospective medical record review in 54 consecutive obese patients. Vancomycin serum concentrations were drawn before the third and fifth dose after initiation. Steady-state concentrations were drawn after the third dose once maintenance dosing was achieved and periodically thereafter.

Results: Within 12 hours after dosing initiation, 48 (89%) study patients exhibited trough concentrations of 10 to 20 µg/mL averaging 14.5 ± 3.2 µg/mL; 51 (94%) study patients exhibited trough concentrations >10 µg/mL within 12 hours after dosing initiation, and 3 (6%) had trough concentrations >20 µg/mL. Thirty-one participants had second trough concentrations drawn within 24 hours of dosing initiation, averaging 15.0 ± 3.1 µg/mL; 24 patients had a total of 32 trough concentrations drawn during maintenance dosing, averaging 15.1 ± 2.5 µg/mL.

Conclusion: Obese-specific, divided-load dosing achieved trough concentrations of 10 to 20 µg/mL for 89% of obese patients within 12 hours of initial dosing and 97% of obese patients within 24 hours of initial dosing while preventing doses given during supratherapeutic trough levels; 97% of troughs measured during steady state were within target range.
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http://dx.doi.org/10.1177/1060028015586423DOI Listing
August 2015

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

Am J Nephrol 2014 17;39(6):543-52. Epub 2014 Jun 17.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Md., USA.

Background: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics.

Methods: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites).

Results: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and β2-microglobulin performed better compared to Cr in estimating RPF, β-trace protein, β2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index.

Conclusion: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.
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http://dx.doi.org/10.1159/000363584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287415PMC
March 2015

Performance of a divided-load intravenous vancomycin dosing strategy for critically ill patients.

Ann Pharmacother 2013 Dec 25;47(12):1611-7. Epub 2013 Oct 25.

Marin General Hospital, Greenbrae, CA, USA.

Background: Current guidelines recommend vancomycin trough concentrations 15 to 20 µg/mL in complicated infections and all trough concentrations above 10 µg/mL.

Objective: We assessed the performance of a novel divided-load protocol designed to attain target trough concentrations within 24 hours of initiation and prevent doses given at concentrations above the target range, in critically ill patients.

Methods: The protocol was evaluated in 79 critically ill patients through retrospective medical record review. Vancomycin serum concentrations were drawn before the third dose after initiation and after any dosing change. Steady-state concentrations were drawn before the fifth or sixth doses. Vancomycin concentrations before the second dose were predicted using a nonparametric expectation maximization algorithm.

Results: Sixty-nine of 79 patients received scheduled doses, and 62 (90%) of the scheduled-dose patients attained therapeutic target concentrations 12 to 24 hours after therapy initiation. Eight scheduled-dose patients weighed > 150% of ideal body weight (IBW) and were significantly more likely to exhibit supratherapeutic trough concentrations before the fifth or sixth doses (P = .0004) compared with patients weighing ≤150% of IBW. Ten of 79 patients (8 dialysis dependent and 2 experiencing acute kidney injury) were dosed in response to measured serum drug concentrations drawn according to the divided-load protocol. All the 8 dialysis-dependent patients (100%) attained therapeutic concentrations 12 hours after therapy initiation.

Conclusion: The divided-load vancomycin dosing strategy achieved measured trough concentrations 15 to 20 µg/mL for most critically ill patients within 24 hours of initial dosing, without allowing doses given during supratherapeutic concentrations.
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http://dx.doi.org/10.1177/1060028013510395DOI Listing
December 2013

Effect of uremic serum and uremic toxins on drug metabolism in human microsomes.

Regul Toxicol Pharmacol 2014 Mar 30;68(2):297-303. Epub 2013 Oct 30.

Division of Drug Safety Research, Food and Drug Administration, Silver Spring, MD, USA.

There is increasing evidence that renal impairment modifies nonrenal drug clearance through drug metabolizing cytochrome P450 (CYP) enzymes. In this study, the direct inhibitory effect of serum from chronic renal failure (CRF) patients receiving dialysis was evaluated in CYP3A4 (testosterone) and CYP2B6 (bupropion) metabolism assays. Human liver microsomes were incubated with ultrafiltered serum collected pre- and post-hemodialysis from ten CRF patients. Additionally, several uremic toxins were evaluated in the CYP3A4 assay. In only three patients was there a significant decrease or increase in testosterone or bupropion metabolism post-dialysis. Urea, mannitol, guanidine, homocysteine, uridine and creatinine had no effect on CYP3A4 metabolism. CMPF, hippuric acid and p-cresol had IC50 values that fell within CRF patient plasma concentrations. The IC50 values for indoxyl sulfate and indole-3-acetic acid were greater than CRF plasma concentrations. The lack of a consistent effect on CYP3A4 or CYP2B6 metabolism by uremic serum may be due in part to the frequency of hemodialysis in these patients which reduced the accumulation of uremic toxins. CMPF, hippuric acid and p-cresol have the ability to inhibit CYP3A4 metabolism at clinical concentrations which may correspond to reports of changes in hepatic metabolism in some CRF patients.
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http://dx.doi.org/10.1016/j.yrtph.2013.10.006DOI Listing
March 2014

Evaluation of hepatic impairment dosing recommendations in FDA-approved product labels.

J Clin Pharmacol 2013 Sep 7;53(9):962-6. Epub 2013 Jul 7.

School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.

Pharmacokinetic (PK) studies in patients with liver disease are an important clinical pharmacology component of drug development. In 2003, FDA released the guidance for industry on "Pharmacokinetics in Patients with Impaired Hepatic Function," which provides recommendations to sponsors on study design, data analysis, and impact on dosing and labeling. We evaluated the quality and consistency of hepatic dosing recommendations, and compared contemporary clinical practice of dosing in patients with impaired hepatic function with product labels. All new molecular entities (NME) and labels approved by the FDA during the period of January 2004 to December 2011 were reviewed. The fraction of the dose hepatically eliminated, quality of hepatic impairment PK studies reported, and any dose recommendations provided in the label and in a tertiary clinical reference (Micromedex) were reviewed. Out of 157 NMEs, 67 met the criteria for evaluation of dosing in hepatic disease. Problem areas were identified related to the lack of specific hepatic metabolism information in 90% of FDA-approved labels, inconsistent terminology, and "use with caution in liver disease" in 27% of NME. Updating the FDA guidance on PK studies in patients with impaired hepatic function could provide a standardized approach to improve the clinical usefulness of this dosing information for practitioners.
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http://dx.doi.org/10.1002/jcph.128DOI Listing
September 2013

Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis.

Hepatology 2014 Apr 30;59(4):1532-42. Epub 2013 Sep 30.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD.

Unlabelled: Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the "bias," "precision," and "accuracy" of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG), and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4-variable MDRD (P = 0.027), and CKD-EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%.

Conclusion: The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.
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http://dx.doi.org/10.1002/hep.26556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883887PMC
April 2014

Glomerular filtration rate equations overestimate creatinine clearance in older individuals enrolled in the Baltimore Longitudinal Study on Aging: impact on renal drug dosing.

Pharmacotherapy 2013 Sep 26;33(9):912-21. Epub 2013 Apr 26.

Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, Maryland.

Objectives: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population.

Design: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010.

Subjects: A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute.

Measurements And Main Results: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively.

Conclusion: The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.
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http://dx.doi.org/10.1002/phar.1282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732548PMC
September 2013

Impact of medication therapy management on underserved, primarily Hispanic patients with diabetes.

Ann Pharmacother 2013 May 12;47(5):665-70. Epub 2013 Apr 12.

School of Pharmacy, University of Maryland, Shady Grove Campus, Rockville, MD, USA.

Background: Diabetes-related complications are more pronounced in Hispanic patients versus patients of other ethnicities. It is documented that medication therapy management (MTM) can improve diabetes outcomes; however, data regarding Hispanic patients are limited.

Objective: To evaluate the impact of MTM on hemoglobin A1c (A1C), blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) in underserved, primarily Hispanic patients who use a safety-net clinic as their medical home.

Methods: A retrospective, observational study of uninsured, primarily Hispanic patients with diabetes who received MTM from October 2009 through March 2011. Patients were stratified into 2 cohorts: A1C less than 9% and A1C greater than or equal to 9%. Patients were also stratified by frequency of MTM visits and insulin use, regardless of A1C. A chart review was conducted to evaluate diabetes-related outcomes pre- and postimplementation of MTM. The primary study outcome was reduction of A1C. Secondary outcomes included reduction of BP and LDL-C and reduction of A1C based on MTM visit frequency or insulin use.

Results: Sixty-four patients with at least 1 MTM visit and pre- and postimplementation A1C data were included. In the cohort with A1C greater than or equal to 9%, mean (SD) A1C values decreased from 10.9% (1.4%) to 8.8% (1.5%) versus the cohort with A1C less than 9%, whose A1C changed minimally, from 7.2% (0.9%) to 7.4% (1.4%). Regardless of their A1C, patients who were using insulin at baseline had a change in A1C of -0.8% (1.5%) versus -0.1% (1.6%) in those who were not using insulin at baseline (p = 0.04); patients who participated in multiple MTM visits had a significant reduction in A1C, from 9% to 8.3% (95% CI -1.26 to -0.03; p = 0.02) compared with patients participating in only 1 MTM visit.

Conclusions: Pharmacist-provided MTM can significantly improve diabetes control in uninsured, primarily Hispanic patients with poorly controlled diabetes and in those who are using insulin. Multiple MTM visits also yielded significant A1C reductions.
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http://dx.doi.org/10.1345/aph.1R648DOI Listing
May 2013

Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1.

Am J Gastroenterol 2012 Nov 23;107(11):1675-83. Epub 2012 Oct 23.

School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.

Objectives: Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90% of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24.

Methods: Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule.

Results: Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P<0.05) and week 72 (SVR) (36.6% vs 54.8%; P<0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P<0.05). Ribavirin exposures ≥4,065 and ≥4,480 ng/ml/day in the first week (AUC(0-7)) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC(0-7) level than CA (P<0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84%) and SVR (AA: 52 vs. CA: 60%) rates in patients who met the ribavirin AUC(0-7) thresholds. Ribavirin AUC(0-7) predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC(0-7) levels increased response rates primarily in AA with the less favorable non-C/C genotypes.

Conclusions: Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.
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http://dx.doi.org/10.1038/ajg.2012.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718255PMC
November 2012

Population pharmacokinetics and pharmacodynamics of ribavirin in patients with chronic hepatitis C genotype 1 infection.

AAPS J 2012 Sep 26;14(3):571-80. Epub 2012 May 26.

School of Pharmacy, University of Maryland, Baltimore, 21201, USA.

We report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n = 71 African American (AA) and n = 73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a two-compartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC(0-7)). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.
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http://dx.doi.org/10.1208/s12248-012-9368-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385833PMC
September 2012

Comparative evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy.

Pharmacotherapy 2011 Nov;31(11):1130-44

University of Utah Hospitals and Clinics, Salt Lake City, Utah, USA.

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.
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http://dx.doi.org/10.1592/phco.31.11.1130DOI Listing
November 2011

Dofetilide dose calculation errors in elderly associated with use of the modification of diet in renal disease equation.

Ann Pharmacother 2011 Jul 28;45(7-8):e44. Epub 2011 Jun 28.

Pharmacy Department, Marin General Hospital, Greenbrae, CA, USA.

Objective: To report 2 cases of drug dosage calculation errors that occurred when the Modification of Diet in Renal Disease (MDRD) equation was used for initiating drug therapy with dofetilide in elderly patients with chronic kidney disease.

Case Summary: An 83-year-old woman and a 92-year-old man were admitted for dofetilide treatment initiation and cardioversion for atrial fibrillation. The estimated glomerular filtration rate (eGFR) determined with use of the MDRD equation was significantly higher than the estimated creatinine clearance (eCrCl) determined with use of the Cockcroft-Gault equation for both cases (85 vs 43 mL/min for the man and 40 vs 24 mL/min for the woman). Initial dofetilide dosages calculated by the MDRD equation were 2-fold higher than those calculated by eCrCl in both cases. Initiation of dose based on the MDRD in the first patient led to a 32% increase in the QTc interval from baseline. Dofetilide therapy was adjusted for QTc interval prolongation based on eCrCl and reinitiated at a lower dose, and the patient did not develop further significant increases in the QTc interval. In the second patient, the lower dose based on eCrCl was initiated and the QTc interval remained within an acceptable range.

Discussion: The initial dosing of dofetilide is based on eCrCl as specified by the drug manufacturer. Recent widespread use and automated reporting of the eGFR by clinical laboratories has tempted some clinicians to consider using eGFR for calculating drug doses. However, recent data suggest that the eGFR, calculated by the MDRD equation, consistently overestimates eCrCl, leading to dose discrepancies, particularly in the elderly. The cases reported here illustrate the drug dose calculation errors that may occur when using the MDRD equation for initiating doses of dofetilide.

Conclusions: Use of the eGFR or MDRD equation for calculation of doses in renal dysfunction has not been validated, and significant drug dose errors have been reported. The use of eGFR to calculate doses of dofetilide should be avoided.
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http://dx.doi.org/10.1345/aph.1Q159DOI Listing
July 2011

Evaluation of renal drug dosing: prescribing information and clinical pharmacist approaches.

Pharmacotherapy 2010 Aug;30(8):776-86

Department of Pharmacy Practice and Science, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.

Study Objective: To characterize renal function parameters reported in United States Food and Drug Administration-approved prescribing information (package inserts), to compare dosage recommendations for patients with impaired renal function between prescribing information and tertiary drug dosing references, and to evaluate renal function quantification methods most commonly used by clinical pharmacists to develop dosage regimens.

Design: Retrospective analysis and Web-based survey.

Data Sources: Prescribing information for all new molecular entities (NMEs) approved from 1998-2007 in which dosing recommendations were proposed for patients with impaired renal function, drug monographs from four tertiary drug dosing references (Micromedex, Lexi-Comp, Epocrates Rx, and American Hospital Formulary Service [AHFS] Drug Information) for all identified NMEs, and a Web-based survey of 204 nephrology and critical care pharmacy practitioners.

Measurements And Main Results: A total of 44 NMEs included renal dosing recommendations in their prescribing information. For all 44 NMEs, prescribing information was reviewed to determine methods to quantify renal function, units of measure reported, and use of chronic kidney disease terminology. The most common index of renal function was creatinine clearance; the Cockcroft-Gault equation was specified in the prescribing information of 11 NMEs. Standardization for body weight was inconsistent, with prescribing information for four NMEs reporting renal function in ml/minute/1.73 m(2). The prescribing information or tertiary sources did not mention use of estimated glomerular filtration rate (eGFR) or the Modification of Diet in Renal Disease Study (MDRD) equation. Epocrates Rx provided the most abbreviated renal dosing information, whereas AHFS Drug Information was the most comprehensive, and Lexi-Comp includes a renal function calculator. Nearly all (86%) clinical pharmacists indicated that automated eGFR is reported at their institutions, although they do not use these predictions for dosing in patients with impaired renal function, and their approaches to renal function estimation varied widely.

Conclusion: Reporting of renal function methods and dosing recommendations for patients with impaired renal function requires standardization in order to ensure optimal dosing. Pharmacy clinicians do not substitute eGFR in place of creatinine clearance for renal dosing, which is consistent with current prescribing information. Studies are needed that will evaluate the validity of using eGFR to predict drug clearance and thereby generate dosage recommendations.
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http://dx.doi.org/10.1592/phco.30.8.776DOI Listing
August 2010

Estimated GFR vs creatinine clearance for drug dosing.

Am J Kidney Dis 2009 Nov;54(5):984-5; author reply 985-6

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http://dx.doi.org/10.1053/j.ajkd.2009.08.015DOI Listing
November 2009

The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training.

Blood Press 2009 ;18(4):171-9

Hypertension, Molecular and Applied Physiology Laboratory, Department of Kinesiology, Temple University, Philadelphia, Pennsylvania 19122, USA.

Objective: The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status.

Methods: Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO(2max) 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF(2alpha) were measured before and after AEXT. Statistically, ANOVA and linear regression were used.

Results: Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF(2alpha) and % Dip.

Conclusions: Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.
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http://dx.doi.org/10.1080/08037050903047160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922419PMC
December 2010
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